11-ketopregnenes and process



Patented May 2, 1950 UNITED STATES PATENT OFFICE ILKETOPREGNENES AND PROCESS Lewis H. Sarett, Princeton, N. J assignor to Merck & 00., Inc., Rahway, N. J a corporation of New Jersey No Drawing. Application August 2, 1946, Serial No. 687,982

8 Claims. (Cl. 260-3973) 1 2 This invention is concerned generally with hereinafter reproduced below in the abbreviated novel chemical compounds of the cyclopentanoform:

dimethylpolyhydrophenanthrene series and processes of preparing the same; more particularly it relates to A -3,ll-diketo-pregnene and 5 A -3,1l-diketo-pregnene and with methods of manufacturing these compounds from readily available starting materials. The new comon, pounds thus produced are of value in the prep- CH aration of adrenal hormones such as dehydro- II Z corticosterone and andrenosterone. They are CH H also of value as a means of establishing the structure of other organic compounds.

These isomeric 3,1l-diketo-pregnenes, subject to this application, can be represented by the following structural formulae:

H O 0 200E H: 19 I H H fla ss 2o 0:011 132: 160132 H: 18 J L14 isl /(13\CH: 9g H--- H: H102 .110 80% 6 A B 5 In the following description of the invention,

\4/[ \6/ the stereochemical relationships of the substitu- H g ents are indicated by the following convention: CH3 (1) A substituent in the C3 position which is l trans to the C10 group, is parenthetically desig- H nated d; (2) The stereochemical relationships of rings 0:0 (3 CH2 A and B are indicated in the formulae as solid H Ci CH3 5 l (IJHa lines representing the valence bond in the cis configuration. 7 H2? 1 In accordance with the present invention, it 0 is now found that A -3,1l-diketo-pregnene and I A -3,1l-diketo-pregnene can be synthesized by reactions indicated generically as follows:

CH: CH: CH:

CH! CH: CH; 011, on by OH, on on, H

Hydrolysis oxidizing -----b Agent (1) y (3) (6) H H H on; em 0H:

CH1 OH OH! on. H om H cm H Hydrolysis oxidizing Y Agent i i R0 HO o H H l i H These formulae for purposes of convenience are wherein R is acyl.

The reactions above indicated are carried out as follows: A stereoisomer of A -3-()-acyloxy-ll-keto-pregnene (1), A -3-(a)-acyloxyabove which are obtained as a mixture when prepared according to the process disclosed in my co.-pending application referred to above, are

reacted with an alkaline hydrolyzing agent under; saponifying conditions to effect hydrolysis of the 3-acyloxy group. Any aqueous. alkaline solution can be employed, but it is presently preferred to effect the hydrolysis by means of methanoli'c potassium hydroxide which is reacted with the starting material at room temperature or preferably under reflux, under which conditions the time required for hydrolysis is approximately hour. The hydrolyzed product isv recovered from the solution by evaporating the solvent therefrom and extracting the pregnene derivative from the inorganic salts by means of an organic solvent such as ether which upon evaporation yields a crude mixture of A and A 3-(a) -hydroxy-1l-keto-pregnene (3 and 4).

The A -34a)hydroxy 11.-keto-pregnene, or A -3.4a) -hydroxy-11-leto-pregnene,,or as presently. preferred, av mixture of these compounds, is then reacted. with an oxidizing agentsuch as chrom-ium trioxide preferably in a solution in an inert solvent such as an aqueous aliphatic acid solution as for example, aqueous acetic acid, aqueous propionic acid and. the. like. It ispreferred to conduct the. reaction at. below about C., under which conditions the time required for the oxidation is approximately 1 hour. In practicing the present invention, the oxidation is preferably carried out under mild conditions in a medium having a pH. of approximately 1 to '1; although the preferred medium is aqueous acetic acid or other lower aliphatic monocarboxylic acids, it is possible to. employ dialkyl ketones such as acetone as a medium for this oxidation reaction. After the oxidation is substantially complete, any excess oxidizing agent is destroyed by addition of a reducing agent such as sodium sulfite and the resulting solution evaporated to. dryness and, redissolved in water and the residue extracted with an organic solvent such as ether. Evaporation of the ether extract yields the desired A -3,11- diketo-pregnene, the M -3,1l-diketo-pregnene or mixtures thereof, depending upon the starting material employed.

The following examples illustrate methods of carrying out the present invention but. it is to be understood that these examples are, given by way of illustration and not of limitation.

Example 1 About 14.6 g. of a mixture containing A and A -3-(a)-acetoxy-ll-keto-pregnene is: dissolved in about 100 cc. of 1.1 N methanolic. potassium hydroxide and the solution is heated under reflux for approximately hour. Substantially all of the methanol is evaporated under reduced pressure, the residual material is diluted with Water, and the aqueous mixture extracted with ether. The ether extract is washed with water, evaporated to dryness on the steam bath to produce a crude mixture of A and A -3-(a)-hydroxyll-keto-pregnene.

About 12.2 g. of this mixture of A: and A 3-(a )-hydroxy-1l-keto-pregnene is dissolved in about 1200 cc. of glacial acetic acid, and a solution containing about 6 g. of chromic acid, about co. of water and, about 120 cc, of glacial acetic acid is added thereto with agitation. The temperature of the resulting solutionis maintained at approximately 16 C. during the addition of the oxidizing agent and for, approximately 1 hour thereafter. About 12 g. of sodium sulfite is then added and the mixture is stirred until the excesschromic acid is reduced. The solution is then evaporated under reduced pressure, the re.- sidual material diluted with water and the aqueous mixture extracted with ether. The ether extract is washed with dilute aqueous potassium carbonate, then with water and finally evaporated to dryness on the steam. bath to produce a crude mixture of A and, A -3,11-diketo-pregnene.

Example 2 The above procedure can be carried out using the individual stereoisomers instead of the mixture of A and A -3-(a) -acetoxy-11-ketopregnenes employed in Example 1. This mixture.

of stereoisomeric 3-(a) -acetoxy-11-keto-pregnenes can be separated by fractional crystallization from methanol to produce substantially pure A -3- (a) -acetoxy-ll-keto-pregnene (M. P. 105- 106 0.), and, A -3(u.) -acetoxy-l1-keto-pregnene (M. P. 86-8? 0).

The A -34a)-acetoxy-ll-keto-pregnene is hydrolyzed by heating with methanolic potassium hydroxide to produce A -3-(a) -hydroxy-11- keto-pregnene. This compound is then oxidized by treatment with a glacial acetic acid solution of chromic acid and the oxidation mixture treated as described in Example 1 to produce an ether extract which upon evaporation yields an oil which is substantially pure A -3-l1-diketopregnene.

M -34a)-acetoxy-11-keto-pregnene is hydrolyzed by heating with methanolic potassium hydroxide and the hydrolysis product recrystallized from aqueous ethanol to produce substantially pure 21 -3400-hydroxy-11-keto-pregmm (M. P.,1-4'7 C., followed by resolidification and remelting at C.)

This compound is then oxidized and the oxidation product worked up as described in Example 1 to produce substantially pure A -3,11-diketopregnene.

I claim:

1. The process of preparing a 3,11-diketo-etiocholane containing a radical in the 17-posltion selected from the class which consists of vinyl and ethylidene radicals from the corresponding 3-acyloxy-1l-keto-etiocholane derivative, which comprises reacting the latter compound with a hydrolyzing agent under saponifying conditions to form the corresponding 3-hydroxy compound; and directly reacting this compound with chromic acid to produce the desired 3,11-diketo-etiocholane derivative.

2. The process which comprises reacting a mixture containing A -3-(a) acetoxy-ll-keto- 2,coa,ase

pregnene and A -34)-acetoxy-11-keto-pregnene with methanolic potassium hydroxide to produce a mixture containing A", -3-()-hydroxy-ll-keto-pregnene and A -3 (a) hydroxy-lL-keto-pregnene; and directly reacting said mixture with chromic acid to produce the corresponding mixture of A -3,11-diketo-pregnene and A -3,1l-diketo-pregnene.

3. The process which comprises reacting a compound selected from the class which consists of A"-"-3-hydroxy-1l-keto-pregnene, and A 3- hydroxy-ll-keto-pregnene, with chromic acid to produce the corresponding stereoisomer selected from" the class which consists of A"#-3,11-diketo pregnene and A"- -3,1l-diketo-pregnene.

4;" The process which comprises reacting a mixture containing A -3-(a)-hydroxy-11 -ketopregnene and A'--" -3-(a) -hydroxy-11-keto-pregneiie with chromic acid to produce the corresponding mixture of A -3,1i-diketo-pregnene and A -3,1I-dIketo-pregnene.

5. A -3- (a) -hydroxy-11-keto-pregnene.

6. A -3-11-diketo-pregnene.

7. A 3,1l-diketo-pregnene.

8. 17 substituted-3,11-diketo etiocholanes in which the l'l-positions substituent is a radical selected from the class which consists-of vinyl and ethylidene radicals. 1 L5 1 LEWIS SARE'I'T.

REFERENCES CITED The following references are of record in the file of this patent: 

1. THE PROCESS OF PREPARING A 3,11-DIKETO-ETIOCHOLANE CONTAINING A RADICAL IN THE 17-POSITION SELECTED FROM THE CLASS WHICH CONSISTS OF VINYL AND ETHYLIDENE RADICALS FROM THE CORRESPONDING 3-ACYLOXY-11-KETO-ETIOCHOLANE DERIVATIVE, WHICH COMPRISES REACTING THE LATTER COMPOUND WITH A HYDROLYZING AGENT UNDER SAPONIFYING CONDITIONS TO FORM THE CORRESPONDING 3-HYDROXY COMPOUND; AND DIRECTLY REACTING THIS COMPOUND WITH CHROMIC ACID TO PRODUCE THE DESIRED 3,11-DIKETO-ETIOCHOLANE DERIVATIVE. 